This invention relates, e.g., to improved agents based metal-containing complex compounds suitable for NMR, X-ray, ultrasound and radiodiagnosis and therapy and a process for their production.
Soon after the discovery of X-rays the most varied substances were experimentally tested as "contrast media" to boost the insufficient contrast of body fluids and soft tissues (Barke, R. Roentgenkontrastmittel X-ray Contrast Media!; Chemie, Physiologie, Klinik VEB Georg Thieme Leipzig, 1970). Heavy elements were suitable as the X-ray absorbing elements of such contrast media. In the course of a long selection and optimization process, finally only contrast media based on iodine (in a stable organic bond) or barium (as a nearly insoluble sulfate) remained. Barium sulfate is used exclusively for visualization of the gastro-intestinal tract and it does not penetrate the body.
With the development of nuclear medicine, e.g., the use of radioactive elements for visualizing certain structures of the organism and pathological areas and especially for functional diagnosis and for radiotherapy, a series of other metals was accepted for in vivo diagnosis. The so-called radiopharmaceuticals used in nuclear medicine contain either a radioactive isotope of iodine (.sup.131 I or .sup.123 I) or preferably a metal such as .sup.99m technetium. These elements are bonded to an organic substance in many cases or, in the case of the radioactive metal isotope, are administered in complexed form. Most often, the stability of the complexing of the metals is such that, during its stay in the body, a more or less large portion of the metal cannot be prevented from being released from its bond to the organic molecule. Thus, in general, the metal ion loses its desired pharmacokinetic and diagnostic properties produced by the complexing, is eliminated only very slowly, disturbs the distribution picture, specific in itself, of the isotope that is still bonded and can exhibit its inherently toxic properties.
At the beginning of the 1980s the interest in metal complexes in diagnostics and therapy increased further. With the development of nuclear spin tomography there arose the question of producing contrast, e.g., signal-influencing substances that could be introduced into the body from the outside. Such substances help to recognize diseases earlier and more accurately. As an effective principle, complex paramagnetic metal ions were introduced which, despite a relatively high dosage (e.g., several grams of complex that contain about 1-2 g of heavy metal) and rapid intravenous injection, have proven to be surprisingly well tolerated (R. Felix, W. Schoerner, M. Laniado, H. P. Niendorf, C. Claussen, W. Fiegler, U. Speck; Radiology 156, 3: 681-688 (1985)). Especially notable is the obviously outstanding acute tolerance of gadolinium-DTPA (European patent application 71564), the most advanced preparation to date in clinical use. The extremely low number and the mild nature of the acute side effects caused by gadolinium-DTPA make it appear suitable also for use in connection with certain X-ray techniques. The necessity of higher dosages and of repeated administration exists for a series of diagnostic problems in nuclear spin tomography and very generally in X-ray diagnosis. In this connection, the question of long-term tolerance of substances containing heavy metals must be given great attention.
Unlike the case for iodine in the iodine-containing X-ray contrast media, the central atoms in the metal-containing complex compounds that are suitable for NMR, X-ray, ultrasound and radiodiagnosis and for therapy are not bonded covalently. The bond of the metal ion is subject to equilibrium with the surroundings which, according to nature, should be on the side of the complex as much as possible. However, a permanent bond can never be attained. In addition it should be noted that the stability constants, some very high, indicated for the complexes relate to unphysiologically high pH values and do not apply for the in vivo situation. Further, in vivo, a concurrence of different ions is involved in the bond to the complexing agents so that the probability for the undesired and sometimes dangerous release of heavy metal ions in the organism increases.
The danger becomes greater
the higher the dosage of the heavy metal complex
the more often the complex is used
the longer it remains in the body
the more chemically or metabolically unstable the complexing agent is and
the more it penetrates the cells of the body.
On the other hand, tissue-specific complexes, for example also those complexes bonded to biomolecules or macromolecules, desired for diagnosis and radiotherapy of certain types of pathological changes are precisely those, in comparison to gadolinium-DTPA, characterized by a longer and more intracellular stay in the body.
Thus, for diverse purposes, there is a need for better tolerated agents in which a release of the heavy metal ion in question from the complex compound is prevented as much as possible.